Proteolytic degradation of Alzheimer's disease amyloid beta-peptide by a metalloproteinase from microglia cells.
The cerebral deposition of amyloid beta-peptide (A beta) is a histopathological characteristic of Alzheimer's disease. Because an impaired clearance of A beta might be involved in the disease, we investigated the proteolytic degradation of synthetic A beta (40-residue peptide) in cultures of glial cells and characterized a protease involved. Whereas rat astrocytes had a very low degradation capacity, cultivated rat microglia cells cleaved A beta. Microglia activity was considerably enhanced by stimulation with lipopolysaccharide and to a lesser extent by phorbol esters. Most of the A beta-degrading activity was released into the medium. By use of selective inhibitors the protease was characterized as a metalloprotease of approximately 200 kDa that was different from neutral endopeptidase (a neuropeptide-degrading enzyme), matrix metalloproteases, or macrophage elastase. Its activity was efficiently reduced by four hydroxamic acid-based zinc-metalloprotease inhibitors that have been shown to inhibit membrane protein secretases (disintegrins). We conclude that activated microglia cells might impair amyloid plaque formation by release of a metalloprotease that degrades soluble A beta, before polymerization.
Mentlein
R
R
Anatomisches Institut, Universität Kiel, Germany.
Ludwig
R
R
Martensen
I
I
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology*; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C078592:amyloid beta-protein (1-40); D008666:Metalloendopeptidases